Fig. 8.

Sugar transport mechanism. Under Apo conditions, vSGLT mainly resides in the inward-facing conformation (step 5) and infrequently isomerizes to the outward-facing conformation (step 1). We hypothesize that, under physiological conditions, the membrane potential drives the conformation of vSGLT toward the outward-facing conformation. This isomerization principally follows the rocking-bundle mechanism with a few deviations such as uncoupled movements of helices belonging to the hash motif (TM3/TM9 and TM4/TM8). On the extracellular side, sodium binding to the outward-facing conformation (step 2) precedes sugar binding, after which the transporter assumes an occluded conformation (step 3) through rigid-body motions of the hash and bundle domains as well as major structural changes in TM10 to occlude the substrate. Before sodium and substrate release, SGLT switches to the inward-open conformation (step 4) and sugar and sodium are released to the intracellular space in a stochastic manner. Inward release results in the Apo inward-facing conformation (step 5) that enables the transport process to reinitialize.